A Man in His 20s With Cough, Unilateral Pleural Effusion, and Nodular Pleural Thickening

      Case Presentation

      A man in his 20s presented to the ED after several months of progressive dyspnea, dry cough, and night sweats. He had no chest pain, fevers, weight loss, or sick contacts. He was previously healthy and took no medications. Social history was notable for 5 pack-years of tobacco use. The patient was sexually active with male partners and had a recent partner infected with human T-lymphotropic virus. The patient worked in set design and window installations, and wore a respirator when working around solvents and resins. From ages 2 to 7 years, he frequently visited buildings at his parents’ workplace that were undergoing asbestos abatement. From ages 7 to 24 years, he frequently visited pottery studios where talc-containing products were used. He frequently visited northern Massachusetts, and infections with Borrelia burgdorferi and Bartonella henselae were common in family members. His stepfather had recently been infected with Anaplasma. There was no family history of cancer.

      Physical Examination Findings

      On admission, the patient was afebrile with a heart rate of 110 beats/min and BP of 132/67 mm Hg. Pulse oximetry was 97% on room air. Examination revealed a thin, well-appearing young man in no acute distress. There were decreased sounds in the left lung field. There was no clubbing or supraclavicular lymphadenopathy. There was no testicular mass. The remainder of the examination produced unremarkable results.

      Diagnostic Studies

      The CBC was normal, with a WBC count of 8.1 × 103/μL with normal differential. The comprehensive metabolic profile was normal. CT imaging of the chest revealed a loculated left pleural effusion and circumferential, nodular left pleural thickening (Fig 1). The effusion displaced the heart to the right. No mediastinal mass was seen. Lymphadenopathy was seen at the left paratracheal position (15 × 10 mm), left hilum (18 × 9 mm), and paraaortic position (9 × 7 mm).
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      Figure 1Initial CT imaging showing a large, loculated pleural effusion, and nodular, irregular scalloped thickening of the pleura. Note tension causing the heart to shift to the right.
      A chest tube was placed and pleural studies showed the following: protein, 5.1 g/dL; lactate dehydrogenase, 208 U/L; and glucose, 57 mg/dL. The effusion was exudative by Light’s criteria. The fluid was red-appearing with 5,000 nucleated cells/μL, with 71% neutrophils on differential. The patient had low-grade fevers that resolved with ongoing drainage of his pleural effusion. A PET scan was performed, which showed increased avidity of the left-sided pleura (standardized uptake value [SUV], 6) (Fig 2), mediastinal lymph nodes (SUV, 4), spleen (SUV, 3.4), and palatine tonsils (SUV, 12).
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      Figure 2PET imaging showing enhancement (standardized uptake value, 6) of the basilar left pleura.
      Flow cytometry of the pleural fluid and peripheral blood was unremarkable, and pleural fluid cytology was negative for malignant cells initially and on repeat sampling. Blood testing for human chorionic gonadotropin and α-fetoprotein produced negative results. The infectious workup for this patient was unremarkable, including negative HIV testing, blood cultures, blood smears, and pleural fluid cultures for bacteria, mycobacteria, and fungi. Serological testing for Borrelia and Bartonella produced negative results. Results of testing for rheumatoid factor, double-stranded DNA, and anti-nuclear antibody were all unremarkable.
      The cardiothoracic surgery service performed a biopsy by video-assisted thoracoscopic surgery (VATS). The patient’s lungs were found to be diffusely adherent throughout the chest. Numerous suspicious-appearing pleural nodules were observed. Frozen sections from these lesions showed epithelioid cell proliferation.
      What is the diagnosis?
      Diagnosis: Malignant mesothelioma, biphasic type


      Mesothelioma is a malignancy of the mesothelial cells that line the pleura, peritoneum, and other body cavities. The incidence of mesothelioma in a person less than 50 years old is 1 case per million persons per year. Most cases of mesothelioma are related to asbestos exposure, and patients experience a latency period between exposure and diagnosis. Studies of malignant pleural mesothelioma (MPM) resulting from environmental asbestos exposure in Turkey endorse a latency period of more than 50 years. The latency period is shorter for patients exposed to occupational levels of asbestos. An analysis of over 1,000 cases of occupational asbestos exposure demonstrated a median time from exposure to death of 32 years.
      There is evidence for a genetic cause in some cases of mesothelioma. Mutations in BAP1 (BRCA1-associated protein 1), a ubiquitination pathway regulator, are associated with an increased risk of mesothelioma. A germline BAP1 mutation syndrome has been identified that predisposes to several cancers including mesothelioma, possibly even in the absence of occupational exposure to asbestos. An analysis of two families with BAP1 mutation syndromes showed that the overall prevalence of cancer was 63.5% in members with a germline BAP1 mutation and 9.1% in members without a mutation. In patients with asbestos exposure, somatic mutations in the genes NF2, p16INK4a, and p14ARF have been identified as drivers for mesothelioma.
      Histologically, there are three subtypes of MPM: sarcomatoid, epithelioid, and biphasic (showing both elements). Survival is worst with sarcomatoid mesothelioma, which comprises about 15% of diagnoses, as these patients tend not to respond to surgery.
      Patients with MPM often present with an insidious onset of nonspecific symptoms, including cough, fatigue, weight loss, dyspnea, or chest pain. Patients may complain of hoarseness and dysphagia from mediastinal involvement. Symptoms are usually present for months prior to diagnosis. A history of exposure to asbestos, for example through working as a shipbuilder, plumber, or pipefitter, should raise the suspicion for mesothelioma. Less commonly, patients present with effects of locally advanced disease. These can include superior vena cava syndrome; abdominal pain, vomiting, and distension secondary to diaphragmatic invasion and abdominal involvement; and neurologic symptoms related to brachial plexopathy. Rarely, patients have been reported to present with paraneoplastic syndromes, including vasculitis and polyneuropathy.
      Diagnostic imaging in MPM can show pleural fluid, pleural thickening (which may be nodular or smooth), and/or a localized pleural mass. A circumferential process on CT scanning is highly suggestive of malignancy. Some experts favor PET-CT to assist in the workup of pleural thickening because PET-CT imaging is > 90% sensitive and has specificity near 90% for malignant pleural thickening. Pleural levels of mesothelin, a glycoprotein tumor biomarker, may be elevated. This finding has good specificity but moderate sensitivity (48%-84%). Other biomarkers currently lacking sufficient sensitivity and specificity for routine clinical use include soluble mesothelin-related protein and fibulin-3 (FBLN3).
      Cytological examination of pleural fluid obtained by thoracentesis is only about 50% sensitive in cases of MPM, despite repeat sampling. Because immunohistochemistry is required to differentiate MPM from adenocarcinoma, tissue biopsy is preferred for diagnosis. Medical thoracoscopy (MT) has similar diagnostic yield and lower rates of complications compared with closed pleural biopsy. In a randomized trial of patients with cytology-negative exudative effusions, MT had a sensitivity for malignancy of 94.1%, compared with 87.5% for CT-guided closed pleural biopsy (not statistically significant). Bronchoscopy with endobronchial ultrasound is an option when there is an obvious mediastinal lymph node to target, but is otherwise not the technique of choice for tissue diagnosis in MPM. Like MT, VATS offers high diagnostic sensitivity (95%) and also allows further surgical techniques to be concurrently performed, such as decortication or placement of a thoracostomy tube for pleural drainage. In patients who do not have a sufficient pleural effusion to allow for a safe VATS approach, thoracotomy may be necessary.
      The rate of complications from tissue diagnosis is low. Both VATS and thoracotomy require general anesthesia, whereas MT requires only local anesthesia. There are no head-to-head trials of MT vs VATS or thoracotomy to compare complication rates. In the literature, serious complications (eg, air leak, pneumonia, or hemorrhage) occur in about 1.5% of patients with MT and 3% to 5% of patients with VATS. Both procedures carry a mortality rate under 1%. An additional concern is seeding of the procedure tract leading to metastases, which occurs in only about 5% of thoracenteses but in up to 16% of VATS and 24% of thoracotomies.
      The differential diagnosis of exudative pleural effusion with pleural thickening includes malignant, infectious, and inflammatory causes. Circumferential pleural thickening is specific for malignancy, including but not limited to lymphoma and metastatic solid tumors like melanoma; cancers of the thyroid, stomach, kidney, ovary, testis, thymus, and prostate; and sarcoma. Solid tumor metastases are favored over lymphoma when imaging shows invasion into the bone or adjacent tissues. Infectious causes of a pleural effusion with pleural thickening include a chronic empyema and tuberculous pleural effusion. In patients with a history of connective tissue disease, rheumatoid pleurisy may also be considered. MPM is difficult to separate from other solid malignancies solely on the basis of history and imaging, requiring tissue sampling to confirm the diagnosis.
      Management of MPM includes a combination of surgery, chemotherapy, and radiation. Prior to surgery, staging of MPM provides prognostic value and determines operability. CT imaging is generally done to guide biopsy and diagnosis and to estimate the macroscopic extent of disease. Fused PET-CT identifies lymph node involvement and distant metastatic disease in 10% of patients without CT evidence of these findings, and is recommended both for improved prognostication and assessment of operability.
      Surgical staging is recommended to confirm imaging evidence of mediastinal lymph node involvement. Retrospective data suggest that endobronchial ultrasound has a higher sensitivity for mediastinal disease—59% vs 28% for mediastinoscopy in one study. The primary staging system for MPM is the TNM system. Previously used staging systems, such as the Brigham and Butchart systems, are outside the scope of this article. All staging systems for mesothelioma suffer from a lack of prognostic precision. As a result, patients with clinical stage I or II disease are often upstaged at the time of surgery.
      There are two primary surgical options for MPM. In pleurectomy and decortication (P/D), the pleura, and sometimes portions of the diaphragm and pericardium, are removed and the lung is left intact. This option is favored for patients whose disease is confined mostly to the parietal pleura, or for patients in whom complete cytoreduction is impossible due to metastasis to a mediastinal or contralateral lymph node. In extrapleural pneumonectomy (EPP), the pleura, lung, hemidiaphragm, and pericardium are resected en bloc on the affected side. This option is often pursued for patients in whom the disease has invaded the visceral pleura or for patients with more robust underlying pulmonary function. EPP carries a higher rate of morbidity (most commonly arrhythmia, patch failure, and ARDS) compared with P/D and a higher rate of mortality (?5% compared with 3% in P/D). The overall survival benefit of one procedure over the other is not clear.
      Chemotherapy is the only modality independently shown to improve survival in MPM. A platinum-based DNA cross-linking agent and pemetrexed, an antifolate agent, in combination represent the standard of care. Bevacizumab, a vascular endothelial growth factor antibody, is also recommended for patients without contraindication. In conjunction with chemotherapy and surgery, radiation therapy may also be recommended in the neoadjuvant and/or adjuvant setting, depending on the surgical plan.
      The prognosis for patients with MPM is poor, with a median survival of 8 to 14 months from diagnosis. Higher stage and sarcomatoid histology are the strongest prognostic factors for poor outcomes. In a clinical prognostic scoring system developed by the European Organisation for Research and Treatment of Cancer, poor prognosis was predicted by lower performance status, high WBC count, male sex, sarcomatoid histology, and the certainty of the diagnosis. Patients with good prognosis based on these variables had a 1-year survival of 40%, whereas survival was 12% for patients with a poor prognosis. Ongoing efforts to improve prognosis include the application of existing immunotherapy drugs such as pembrolizumab, a programmed cell death protein 1 antibody. Novel antibodies against mesothelin, a protein commonly overexpressed in MPM, are being studied. Gene therapy techniques are being explored.

       Clinical Course

      The differential diagnosis for this patient presenting with nodular pleural thickening and pleural effusion was broad. Non-Hodgkin's lymphoma was believed to be most likely given the patient’s young age, night sweats, and fluorodeoxyglucose-avid spleen and lymph nodes. Although the nodular, circumferential pleural thickening on the patient’s imaging was highly consistent with mesothelioma, this was thought unlikely because of the patient’s young age. We also considered a “pseudo-mesothelioma” caused by primary adenocarcinoma of the lung. Metastatic disease was on the differential, including melanoma and renal cell, thyroid, and gastrointestinal malignancy. Germ cell neoplasm was unlikely given the lack of a mediastinal mass. Infections, for example, a parapneumonic effusion from Streptococcus pneumoniae or Mycobacterium tuberculosis, were less likely given the radiographic appearance of nodular pleural thickening. These infections were ruled out with negative pleural fluid cultures. The patient’s history of family members with severe Bartonella infections raised the possibility of that as the causative organism, but testing was negative. Ultimately, the patient was diagnosed with malignant mesothelioma after VATS biopsy. The biopsy was consistent with biphasic mesothelioma (Figs 3 and 4).
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      Figure 3A and B, Hematoxylin and eosin stain of the patient’s pathology sample, showing epithelioid (magnification, ×150) (A) and sarcomatoid (magnification, ×100) (B) elements consistent with biphasic mesothelioma.
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      Figure 4Nuclear and cytoplasmic staining for calretinin, supportive of the diagnosis of mesothelioma (magnification, ×150).
      The patient underwent mediastinoscopy that confirmed no involvement of the mediastinal or contralateral lymph nodes. Genetic testing was negative for germline or somatic mutations in BAP1. Following an interdisciplinary discussion with the thoracic and medical oncology services, the patient was referred for EPP followed by adjuvant chemoradiation.

      Clinical Pearls

      • 1.
        The differential diagnosis of a unilateral pleural effusion with nodular pleural thickening favors malignancies including lymphoma, mesothelioma, pseudo-mesothelioma secondary to lung adenocarcinoma, and metastatic melanoma; and renal cell, breast, stomach, kidney, ovary, thymus, prostate, and thyroid carcinoma. Infectious causes of a pleural effusion with pleural thickening include a chronic empyema and, in the appropriate clinical setting, a tuberculous pleural effusion. In patients with a history of connective tissue disease, consider rheumatoid pleurisy.
      • 2.
        Mesothelioma is not usually distinguishable from primary lung cancer or metastatic solid malignancies based on clinical history, imaging, and pleural fluid cytology. Thoracoscopic biopsy or VATS is necessary for a definitive diagnosis.
      • 3.
        Staging of MPM provides prognostic value and also determines operability. Staging includes imaging, including PET-CT. Pathologic staging is essential to identify which patients have resectable disease. Treatment includes surgery depending on the extent of disease and functional status, as well as chemotherapy and radiation.
      • 4.
        Pemetrexed and a platinum agent are the standard for chemotherapy, plus or minus bevacizumab. Ongoing efforts to improve the prognosis of this disease include trials with pembrolizumab. Novel antibodies against mesothelin, a protein commonly overexpressed in MPM, are being studied.
      • 5.
        At present, the prognosis of malignant pleural mesothelioma is poor, with a median survival of 8 to 14 months from diagnosis. Stage and histology are the strongest prognostic factors. Other factors associated with worse outcomes include sarcomatoid histology, male sex, and poor functional status.


      Financial/nonfinancial disclosures: None declared.
      Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.